Method for making analgesics

ABSTRACT

Improved analgesic oxymorphone hydrochloride contains less than 10 ppm of alpha, beta unsaturated ketones and pharmaceutical preparations comprising such oxymorphone hydrochloride. The oxymorphone hydrochloride is produced by reducing a starting material oxymorphone hydrochloride using gaseous hydrogen and under specified acidity, solvent system and temperature conditions. A specific polymorph of oxymorphone hydrochloride may be obtained by hydration.

FIELD OF THE INVENTION

This invention concerns an improved method for making analgesics, moreespecially for making the opiate oxymorphone as its hydrochloride.

BACKGROUND OF THE INVENTION

Oxymorphone, generally administered in the form of its hydrochloridesalt, is a potent semi-synthetic opiate analgesic, for the relief ofmoderate to severe pain, and has been approved for use since 1959. Itcan be administered as an injectable solution, suppository, tablet orextended release tablet. It is desirable to develop high purity forms ofoxymorphone and a method for its synthesis.

Several methods for synthesising oxymorphone from compounds isolatedfrom the opium poppy or compounds derived therefrom are known, forexample, starting from morphine, thebaine, or from oxycodone. Thereremains the need for methods which permit the formation of oxymorphonewith low contamination of alpha, beta unsaturated ketones. The presentinvention provides an improved oxymorphone product and a method forproducing such oxymorphone.

U.S. Pat. No. 7,129,248 claims a process for producing oxycodonehydrochloride with less than 25 ppm of 14-hydroxycodeinone, byhydrogenating oxycodone having greater than 100 ppm 14-hydroxycodeinone.The synthetic route to oxycodone taught in US '248 starts from thebaineand produces 14-hydroxycodeinone as an intermediate product and8,14-dihydroxy-7,8-dihydrocodeinone as a by-product resulting fromover-oxidation of thebaine. During conversion of oxycodone free base tothe hydrogen chloride salt, the by-product may undergo acid-catalyseddehydration and be converted into 14-hydroxycodeinone. Thus the finaloxycodone hydrogen chloride salt contains unreacted 14-hydroxycodeinoneas well as 14-hydroxycodeinone derived from the by-product8,14-dihydroxy-7,8-dihydrocodeinone. A hydrogenation step is claimed toreduce contents of 14-hydroxycodeinone from at least 100 ppm to lessthan 25 ppm.

SUMMARY OF THE INVENTION

The present invention provides an oxymorphone hydrochloride productcontaining less than 10 ppm of alpha, beta unsaturated ketones.

The invention also provides a method of purifying oxymorphonehydrochloride to yield an oxymorphone hydrochloride product containingless than 10 ppm of alpha, beta unsaturated ketones, which methodcomprises reducing a starting material oxymorphone hydrochloride in astrongly acid water and alcohol solvent, using gaseous hydrogen at atemperature in the range from 60 to 70° C. Reduction is suitably carriedout for a period of at least 20 hours, but in another embodiment,reduction is carried out for 1 to 20 hours.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be described below with reference to the drawing, inwhich:

FIG. 1 is the Powder X-Ray Diffraction pattern collected for a hydratedoxymorphone hydrochloride product made according to Example 3.2D.

DETAILED DESCRIPTION OF THE INVENTION

Preferably, the solvent is ethanol/water, although other water misciblealcohols, such as isopropanol and n-propanol, may be used. The reactionmedium is very acidic, preferably by incorporating at least twoequivalents of hydrochloric acid. A pH of less than 1 is desirable.

The reaction temperature is most preferably maintained at about 65° C.Hydrogen is conveniently supplied to the reaction vessel at 2.41 barpressure.

The method of the invention has been able to reduce starting materialoxymorphone hydrochloride having very high (of the order of 0.3 to 0.5%,or 3,000 to 5,000 ppm) content of alpha, beta unsaturated ketones toless than 10 ppm, and in many cases to undetectable levels (by HPLC).

The starting material oxymorphone hydrochloride may be an isolated ornon-isolated material. Desirably, it has been obtained by the formationof the hydrogen chloride salt by heating oxymorphone free base in thepresence of hydrochloric acid and an alcohol/water reaction medium.Suitable temperatures are 60-70° C. It can be seen that the reactionmedium is ideal for the reduction of the method of the invention, sothat it is generally not necessary to isolate the oxymorphonehydrochloride. However, the starting material oxymorphone hydrochloridemay be isolated from the reaction medium or may be from another source.

The oxymorphone free base is itself preferably prepared by a reductionof 14-hydroxymorphinone. This may be carried out in a single- ortwo-stage process. The reduction is preferably carried out in aceticacid using gaseous hydrogen and a palladium on carbon catalyst.Preferred temperatures are of the order of 30° C. The base isprecipitated by adding aqueous ammonia (NH₄OH).

This reduction may be in the presence of the reaction medium to which isadded dichloromethane in methanol, Florasil and n-propanol.

The 14-hydroxymorphinone itself is most suitably prepared byhydroxylation of oripavine, using hydrogen peroxide in the presence offormic acid.

Oripavine is a known compound, which is extractable from poppy straw.The strain developed in Tasmania to be a high-Thebaine-yielding strainalso produces higher than normal levels of oripavine.

The process of the invention is highly flexible, permitting manyreaction steps to be carried out without isolation of intermediateproducts, whilst still retaining high (of the order of 50%) overallyields from oripavine, as well as remarkably high purity. Underfavourable conditions, the presence of alpha, beta unsaturated ketonesis undetectable by conventional means such as HPLC, but the skilledperson can readily achieve less than 10 ppm contamination. The processof the invention has been successfully carried out at kilogram scale.

The oxymorphone hydrochloride having less than 10 ppm of alpha, betaunsaturated ketones can be incorporated into pharmaceutical dosageforms, e.g., by admixtures of the oxymorphone hydrochloride having lessthan 10 ppm of alpha, beta unsaturated ketones with conventionalexcipients, i.e., pharmaceutically acceptable organic or inorganiccarrier substances. For oral formulations, the dosage forms can providea sustained release of the active component. Suitable pharmaceuticallyacceptable carriers include but are not limited to, alcohols, gumarabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelate,carbohydrates such as lactose, amylose or starch, magnesium stearate,talc, silicic acid, viscous paraffin, perfume oil, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxy-methylcellulose, polyvinylpyrrolidone, etc. The pharmaceuticalpreparations can be sterilized and if desired mixed with auxiliaryagents, e.g., lubricants, disintegrants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressurebuffers, colouring, flavouring and/or aromatic substances and the like.The compositions intended for oral use may be prepared according to anymethod known in the art and such compositions may contain one or moreagents selected from the group consisting of inert, non-toxicpharmaceutically acceptable excipients that are suitable for themanufacture of tablets. Such excipients include, for example an inertdiluent such as lactose; granulating and disintegrating agents such ascornstarch; binding agents such as starch; and lubricating agents suchas magnesium stearate. The tablets may be uncoated or they may be coatedby known techniques for elegance or to delay release of the activeingredients. Formulations for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertdiluent. The oral dosage forms of the present invention may be in theform of tablets (sustained release and/or immediate release), troches,lozenges, powders or granules, hard or soft capsules, microparticles(e.g., microcapsules, microspheres and the like), buccal tablets,solutions, suspensions, etc.

In certain embodiments, the present invention provides for a method oftreating pain by administering to a human patient the dosage formsdescribed herein.

When the dosage form is oral, the dosage form of the present inventioncontains from about 1 mg to about 40 mg of oxymorphone hydrochloridehaving less than 10 ppm of alpha, beta unsaturated ketones. Particularlypreferred dosages are about 5 mg, about 10 mg, about 20 mg or about 40mg however other dosages may be used as well. The oxymorphonehydrochloride having less than 10 ppm of alpha, beta unsaturated ketonescan also be formulated with suitable pharmaceutically acceptableexcipients to provide a sustained release of having less than 10 ppm ofalpha, beta unsaturated ketones. Such formulations can be prepared inaccordance with US 2003/129230 A1, US 2003/129234 A1 and US 2003/157167A1.

The oxymorphone hydrochloride having less than 10 ppm of alpha, betaunsaturated ketones can be formulated as a sustained release oralformulation in any suitable tablet, coated tablet or multiparticulateformulation known to those skilled in the art. The sustained releasedosage form may include a sustained release material that isincorporated into a matrix along with the oxymorphone salt thereof.

The sustained release dosage form may optionally comprise particlescontaining oxymorphone hydrochloride having less than 10 ppm of alpha,beta unsaturated ketones. In certain embodiments, the particles have adiameter from about 0.1 mm to about 2.5 mm, preferably from about 0.5 mmto about 2 mm. Preferably, the particles are film coated with a materialthat permits release of the active at a sustained rate in an aqueousmedium. The film coat is chosen so as to achieve, in combination withthe other stated properties, desired release properties. The sustainedrelease coating formulations of the present invention should preferablybe capable of producing a strong, continuous film that is smooth andelegant, capable of supporting pigments and other coating additives,non-toxic, inert, and tack-free.

Coated Beads

In certain embodiments of the present invention a hydrophobic materialis used to coat inert pharmaceutical beads such as nu pariel 18/20beads, and a plurality of the resultant solid sustained release beadsmay thereafter be placed in a gelatin capsule in an amount sufficient toprovide an effective sustained release dose when ingested and contactedby an environmental fluid, e.g., gastric fluid or dissolution media.

The sustained release bead formulations of the present invention slowlyrelease the active component of the present invention, e.g., wheningested and exposed to gastric fluids, and then to intestinal fluids.The sustained release profile of the formulations of the invention canbe altered, for example, by varying the amount of overcoating with thehydrophobic material, altering the manner in which a plasticiser isadded to the hydrophobic material, by varying the amount of plasticiserrelative to hydrophobic material, by the inclusion of additionalingredients or excipients, by altering the method of manufacture, etc.The dissolution profile of the ultimate product may also be modified,for example, by increasing or decreasing the thickness of the retardantcoating.

Spheroids or beads coated with the agent(s) of the present are prepared,e.g., by dissolving the agent(s) in water and then spraying the solutiononto a substrate, for example, nu pariel 18/20 beads, using a Wusterinsert. Optionally, additional ingredients are also added prior tocoating the beads in order to assist the binding of the active to thebeads, and/or to color the solution, etc. For example, a product thatincludes hydroxypropylmethylcellulose, etc with or without colorant(e.g., Opadry™, commercially available from Colorcon, Inc.) may be addedto the solution and the solution mixed (e.g., for about 1 hour) prior toapplication of the same onto the beads. The resultant coated substrate,in these example beads, may then be optionally overcoated with a barrieragent, to separate the active component(s) from the hydrophobicsustained release coating. An example of a suitable barrier agent is onewhich comprises hydroxypropylmethylcellulose. However, any film-formerknown in the art may be used. It is preferred that the barrier agentdoes not affect the dissolution rate of the final product.

The beads may then be overcoated with an aqueous dispersion of thehydrophobic material. The aqueous dispersion of hydrophobic materialpreferably further includes an effective amount of plasticiser, e.g.triethyl citrate. Pre-formulated aqueous dispersions of ethylcellulose,such as Aquacoat™ or Surelease™, may be used. If Surelease™ is used, itis not necessary to separately add a plasticiser. Alternatively,pre-formulated aqueous dispersions of acrylic polymers such as Eudragit™can be used.

The coating solutions of the present invention preferably contain, inaddition to the film-former, plasticiser, and solvent system (i.e.,water), a colorant to provide elegance and product distinction. Colourmay be added to the solution of the therapeutically active agentinstead, or in addition to the aqueous dispersion of hydrophobicmaterial. For example, colour may be added to Aquacoat™ via the use ofalcohol or propylene glycol based colour dispersions, milled aluminiumlakes and opacifiers such as titanium dioxide by adding colour withshear to water soluble polymer solution and then using low shear to theplasticised Aquacoat™. Alternatively, any suitable method of providingcolour to the formulations of the present invention may be used.Suitable ingredients for providing colour to the formulation when anaqueous dispersion of an acrylic polymer is used include titaniumdioxide and colour pigments, such as iron oxide pigments. Theincorporation of pigments, may, however, increase the retard effect ofthe coating.

Plasticised hydrophobic material may be applied onto the substratecomprising the agent(s) by spraying using any suitable spray equipmentknown in the art. In a preferred method, a Wurster fluidised-bed systemis used in which an air jet, injected from underneath, fluidises thecore material and effects drying while the acrylic polymer coating issprayed on. A sufficient amount of the hydrophobic material to obtain apredetermined sustained release of the agent(s) when the coatedsubstrate is exposed to aqueous solutions, e.g. gastric fluid, may beapplied. After coating with the hydrophobic material, a further overcoatof a film-former, such as Opadry™, is optionally applied to the beads.This overcoat is provided, if at all, in order to substantially reduceagglomeration of the beads.

The release of the agent(s) from the sustained release formulation ofthe present invention can be further influenced, i.e., adjusted to adesired rate, by the addition of one or more release-modifying agents,or by providing one or more passageways through the coating. The ratioof hydrophobic material to water soluble material is determined by,among other factors, the release rate required and the solubilitycharacteristics of the materials selected.

The release-modifying agents, which function as pore-formers may beorganic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in an environment of use. Thepore-formers may comprise one or more hydrophilic materials such ashydroxypropylmethylcellulose.

The sustained release coatings of the present invention can also includeerosion-promoting agents such as starch and gums.

The sustained release coatings of the present invention can also includematerials useful for making microporous lamina in the environment ofuse, such as polycarbonates comprised of linear polyesters of carbonicacid in which carbonate groups reoccur in the polymer chain.

The release-modifying agent may also comprise a semi-permeable polymer.

In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

The sustained release coatings of the present invention may also includean exit means comprising at least one passageway, orifice, or the like.The passageway may be formed by such methods as those disclosed in U.S.Pat. No. 3,845,770, U.S. Pat. No. 3,916,899, U.S. Pat. No. 4,063,064 andU.S. Pat. No. 4,088,864.

Matrix Formulations

In other embodiments of the present invention, the sustained releaseformulation is achieved via a matrix optionally having a sustainedrelease coating as set forth herein. The materials suitable forinclusion in a sustained release matrix may depend on the method used toform the matrix.

For example, a matrix in addition to the oxymorphone hydrochloridehaving less than 10 ppm of alpha, beta unsaturated ketones may include:hydrophilic and/or hydrophobic materials, such as gums, celluloseethers, acrylic resins, protein derived materials. The list is not meantto be exclusive, any pharmaceutically acceptable hydrophobic material orhydrophilic material which is capable of imparting sustained release ofthe agent(s) and which melts (or softens to the extent necessary to beextruded) may be used in accordance with the present invention.

Digestible, long chain (C₈-C₅₀, especially C₁₂-C₄₀), substituted orunsubstituted hydrocarbons, such as fatty acids, fatty alcohols,glyceryl esters of fatty acids, mineral and vegetable oils and waxes,and stearyl alcohol; and polyalkylene glycols. Of these polymers,acrylic polymers, especially Eudragit™. RSPO—the cellulose ethers,especially hydroxyalkylcelluloses and carboxyalkylcelluloses, arepreferred. The oral dosage form may contain between 1% and 80% (byweight) of at least one hydrophilic or hydrophobic material.

When the hydrophobic material is a hydrocarbon, the hydrocarbonpreferably has a melting point of between 25° C. and 90° C. Of the longchain hydrocarbon materials, fatty (aliphatic) alcohols are preferred.The oral dosage form may contain up to 60% (by weight) of at least onedigestible, long chain hydrocarbon.

Preferably, the oral dosage form contains up to 60% (by weight) of atleast one polyalkylene glycol.

The hydrophobic material is preferably selected from the groupconsisting of alkylcelluloses, acrylic and methacrylic acid polymers andcopolymers, shellac, zein, hydrogenated castor oil, hydrogenatedvegetable oil, or mixtures thereof. In certain preferred embodiments ofthe present invention, the hydrophobic material is a pharmaceuticallyacceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamine copolymer,poly(methyl methacrylate), poly(methacrylic acid) (anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. In other embodiments, the hydrophobicmaterial is selected from materials such as hydroxyalkylcelluloses suchas hydroxypropylmethylcellulose and mixtures of the foregoing.

Preferred hydrophobic materials are water-insoluble with more or lesspronounced hydrophilic and/or hydrophobic trends. Preferably, thehydrophobic materials useful in the invention have a melting point fromabout 25° C. to about 200° C., preferably from about 45° C. to about 90°C. Specifically, the hydrophobic material may comprise natural orsynthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl,cetyl or preferably cetostearyl alcohol), fatty acids, including but notlimited to fatty acid esters, fatty acid glycerides (mono-, di-, andtri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearicaid, stearyl alcohol and hydrophobic and hydrophilic materials havinghydrocarbon backbones. Suitable waxes include, for example, beeswax,glycowax, castor wax and carnauba wax. For the purposes of the presentinvention, a wax-like substance is defined as any material that isnormally solid at room temperature and has a melting point of from about25° C. to about 100° C.

Suitable hydrophobic materials which may be used in accordance with thepresent invention include digestible, long chain (C₈-C₅₀, especiallyC₁₂-C₄₀), substituted or unsubstituted hydrocarbons, such as fattyacids, fatty alcohols, glyceryl esters of fatty acids, mineral andvegetable oils and natural and synthetic waxes. Hydrocarbons having amelting point of between 25° C. and 90° C. are preferred. Of the longchain hydrocarbon materials, fatty (aliphatic) alcohols are preferred incertain embodiments. The oral dosage form may contain up to 60% (byweight) of at least one digestible, long chain hydrocarbon. Preferably,a combination of two or more hydrophobic materials are included in thematrix formulations. If an additional hydrophobic material is included,it is preferably selected from natural and synthetic waxes, fatty acids,fatty alcohols, and mixtures of the same. Examples include beeswax,carnauba wax, stearic acid and stearyl alcohol. This list is not meantto be exclusive.

One particular suitable matrix comprises at least one water solublehydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferably C₁₄-C₂₂,aliphatic alcohol and, optionally, at least one polyalkylene glycol. Theat least one hydroxyalkyl cellulose is preferably a hydroxy (C₁ to C₆)alkyl cellulose, such as hydroxypropylcellulose,hydroxypropyl-methylcellulose and, especially, hydroxyethylcellulose.The amount of the at least one hydroxyalkyl cellulose in the presentoral dosage form will be determined, inter alia, by the precise rate ofoxymorphone hydrochloride release required. The at least one aliphaticalcohol may be, for example, lauryl alcohol, myristyl alcohol or stearylalcohol. In particularly preferred embodiments of the present oraldosage form, however, the at least one aliphatic alcohol is cetylalcohol or cetostearyl alcohol. The amount of the at least one aliphaticalcohol in the present oral dosage form will be determined, as above, bythe precise rate of opioidoxycmorphone release required. It will alsodepend on whether at least one polyalkylene glycol is present in orabsent from the oral dosage form. In the absence of at least onepolyalkylene glycol, the oral dosage form preferably contains between20% and 50% (by wt) of the at least one aliphatic alcohol. When at leastone polyalkylene glycol is present in the oral dosage form, then thecombined weight of the at least one aliphatic alcohol and the at leastone polyalkylene glycol preferably constitutes between 20% and 50% (bywt) of the total dosage.

In one embodiment, the ratio of, e.g., the at least one hydroxyalkylcellulose or acrylic resin to the at least one aliphaticalcohol/polyalkylene glycol determines, to a (w/w) of the at least onehydroxyalkyl cellulose to the at least one aliphaticalcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred, with aratio of between 1:3 and 1:4 being particularly preferred.

The at least one polyalkylene glycol may be, for example, polypropyleneglycol or, preferably, polyethylene glycol. The number average molecularweight of the at least one polyalkylene glycol is preferably between1,000 and 15,000 especially between 1,500 and 12,000.

Another suitable sustained release matrix would comprise analkylcellulose (especially ethyl cellulose), a C₁₂ to C₃₆ aliphaticalcohol and, optionally, a polyalkylene glycol.

In another preferred embodiment, the matrix includes a pharmaceuticallyacceptable combination of at least two hydrophobic materials.

In addition to the above ingredients, a sustained release matrix mayalso contain suitable quantities of other materials, e.g. diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

Matrix—Particulates

In order to facilitate the preparation of a solid, sustained release,oral dosage form according to this invention, any method of preparing amatrix formulation known to those skilled in the art may be used. Forexample incorporation in the matrix may be effected, for example, by (a)forming granules comprising at least one water soluble hydroxyalkylcellulose, and the oxymorphone hydrochloride having less than 10 ppm ofalpha, beta unsaturated ketones; (b) mixing the hydroxyalkyl cellulosecontaining granules with at least one C₁₂ to C₃₆ aliphatic alcohol; and(c) optionally, compressing and shaping the granules. Preferably, thegranules are formed by wet granulating the hydroxalkyl cellulosegranules with water.

In yet other alternative embodiments, a spheronising agent, togetherwith the active component can be spheronised to form spheroids.Microcrystalline cellulose is a preferred spheronising agent. A suitablemicrocrystalline cellulose is, for example, the material sold as AvicelPH 101 (Trade Mark, FMC Corporation). In such embodiments, in additionto the active ingredient and spheronising agent, the spheroids may alsocontain a binder. Suitable binders, such as low viscosity, water solublepolymers, will be well known to those skilled in the pharmaceutical art.However, water soluble hydroxy lower alkyl cellulose, such ashydroxypropyl-cellulose, are preferred. Additionally (or alternatively)the spheroids may contain a water insoluble polymer, especially anacrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethylacrylate copolymer, or ethyl cellulose. In such embodiments, thesustained release coating will generally include a hydrophobic materialsuch as (a) a wax, either alone or in admixture with a fatty alcohol; or(b) shellac or zein.

Melt Extrusion Matrix

Sustained release matrices can also be prepared via melt-granulation ormelt-extrusion techniques. Generally, melt-granulation techniquesinvolve melting a normally solid hydrophobic material, e.g. a wax, andincorporating a powdered drug therein. To obtain a sustained releasedosage form, it may be necessary to incorporate an additionalhydrophobic substance, e.g. ethylcellulose or a water-insoluble acrylicpolymer, into the molten wax hydrophobic material. Examples of sustainedrelease formulations prepared via melt-granulation techniques are foundin U.S. Pat. No. 4,861,598.

The additional hydrophobic material may comprise one or morewater-insoluble wax-like thermoplastic substances possibly mixed withone or more wax-like thermoplastic substances being less hydrophobicthan said one or more water-insoluble wax-like substances. In order toachieve constant release, the individual wax-like substances in theformulation should be substantially non-degradable and insoluble ingastrointestinal fluids during the initial release phases. Usefulwater-insoluble wax-like substances may be those with a water-solubilitythat is lower than about 1:5,000 (w/w).

In addition to the above ingredients, a sustained release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colourants, flavourants andglidants that are conventional in the pharmaceutical art. The quantitiesof these additional materials will be sufficient to provide the desiredeffect to the desired formulation.

In addition to the above ingredients, a sustained release matrixincorporating melt-extruded multiparticulates may also contain suitablequantities of other materials, e.g. diluents, lubricants, binders,granulating aids, colourants, flavourants and glidants that areconventional in the pharmaceutical art in amounts up to about 50% byweight of the particulate if desired.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms are described in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986).

Melt Extrusion Multiparticulates

The preparation of a suitable melt-extruded matrix according to thepresent invention may, for example, include the steps of blending theoxymorphone hydrochloride having less than 10 ppm of alpha, betaunsaturated ketones together with at least one hydrophobic material andpreferably the additional hydrophobic material to obtain a homogeneousmixture. The homogeneous mixture is then heated to a temperaturesufficient to at least soften the mixture sufficiently to extrude thesame. The resulting homogeneous mixture is then extruded to formstrands. The extrudate is preferably cooled and cut intomultiparticulates by any means known in the art. The strands are cooledand cut into multiparticulates. The multiparticulates are then dividedinto unit doses. The extrudate preferably has a diameter of from about0.1 mm to about 5 mm and provides sustained release of thetherapeutically active agent for a time period of from about 8 hours toabout 24 hours.

An optional process for preparing the melt extrusions of the presentinvention includes directly metering into an extruder a hydrophobicmaterial, the oxymorphone hydrochloride having less than 10 ppm ofalpha, beta unsaturated ketones, and an optional binder; heating thehomogenous mixture; extruding the homogenous mixture to thereby formstrands; cooling the strands containing the homogeneous mixture; cuttingthe strands into particles having a size from about 0.1 mm to about 12mm; and dividing said particles into unit doses. In this aspect of theinvention, a relatively continuous manufacturing procedure is realized.

The diameter of the extruder aperture or exit port can also be adjustedto vary the thickness of the extruded strands. Furthermore, the exitpart of the extruder need not be round; it can be oblong, rectangular,etc. The exiting strands can be reduced to particles using a hot wirecutter, guillotine, etc.

The melt extruded multiparticulate system can be, for example, in theform of granules, spheroids or pellets depending upon the extruder exitorifice. For the purposes of the present invention, the terms“melt-extruded multiparticulate(s)” and “melt-extruded multiparticulatesystem(s)” and “melt-extruded particles” shall refer to a plurality ofunits, preferably within a range of similar size and/or shape andcontaining one or more active agents and one or more excipients,preferably including a hydrophobic material as described herein. In thisregard, the melt-extruded multiparticulates will be of a range of fromabout 0.1 mm to about 12 mm in length and have a diameter of from about0.1 mm to about 5 mm. In addition, it is to be understood that themelt-extruded multiparticulates can be any geometrical shape within thissize range. Alternatively, the extrudate may simply be cut into desiredlengths and divided into unit doses of the therapeutically active agentwithout the need of a spheronisation step.

In one preferred embodiment, oral dosage forms are prepared to includean effective amount of melt-extruded multiparticulates within a capsule.For example, a plurality of the melt-extruded multiparticulates may beplaced in a gelatin capsule in an amount sufficient to provide aneffective sustained release dose when ingested and contacted by gastricfluid.

In another preferred embodiment, a suitable amount of themultiparticulate extrudate is compressed into an oral tablet usingconventional tabletting equipment using standard techniques. Techniquesand compositions for making tablets (compressed and moulded), capsules(hard and soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980).

In yet another preferred embodiment, the extrudate can be shaped intotablets as set forth in U.S. Pat. No. 4,957,681, described in additionaldetail above.

Optionally, the sustained release melt-extruded multiparticulate systemsor tablets can be coated, or the gelatin capsule containing themultiparticulates can be further coated, with a sustained releasecoating such as the sustained release coatings described above. Suchcoatings preferably include a sufficient amount of hydrophobic materialto obtain a weight gain level from about 2% to about 30%, although theovercoat may be greater depending upon the desired release rate, amongother things.

The melt-extruded unit dosage forms of the present invention may furtherinclude combinations of melt-extruded particles before beingencapsulated. Furthermore, the unit dosage forms can also include anamount of an immediate release agent for prompt release. The immediaterelease agent may be incorporated, e.g., as separate pellets within agelatin capsule, or may be coated on the surface of themultiparticulates after preparation of the dosage forms (e.g., sustainedrelease coating or matrix-based). The unit dosage forms of the presentinvention may also contain a combination of sustained release beads andmatrix multiparticulates to achieve a desired effect.

The sustained release formulations of the present invention preferablyslowly release the agent(s), e.g. when ingested and exposed to gastricfluids, and then to intestinal fluids. The sustained release profile ofthe melt-extruded formulations of the invention can be altered, forexample, by varying the amount of retardant, i.e., hydrophobic material,by varying the amount of plasticiser relative to hydrophobic material,by the inclusion of additional ingredients or excipients, by alteringthe method of manufacture, etc.

In other embodiments of the invention, the melt extruded material isprepared without the inclusion of the oxymorphone hydrochloride havingless than 10 ppm of alpha, beta unsaturated ketones, which can be addedthereafter to the extrudate. Such formulations typically will have theagents blended together with the extruded matrix material, and then themixture would be tableted in order to provide a slow releaseformulation.

Coatings

The dosage forms of the present invention may optionally be coated withone or more materials suitable for the regulation of release or for theprotection of the formulation. In one embodiment, coatings are providedto permit either pH-dependent or pH-independent release. A pH-dependentcoating serves to release the active in desired areas of thegastro-intestinal (GI) tract, e.g. the stomach or small intestine, suchthat an absorption profile is provided which is capable of providing atleast about eight hours and preferably about twelve hours to up to abouttwenty-four hours of analgesia to a patient. When a pH-independentcoating is desired, the coating is designed to achieve optimal releaseregardless of pH-changes in the environmental fluid, e.g., the GI tract.It is also possible to formulate compositions that release a portion ofthe dose in one desired area of the GI tract, e.g., the stomach, andrelease the remainder of the dose in another area of the GI tract, e.g.,the small intestine.

Formulations according to the invention that utilize pH-dependentcoatings to obtain formulations may also impart a repeat-action effectwhereby unprotected drug is coated over the enteric coat and is releasedin the stomach, while the remainder, being protected by the entericcoating, is released further down the gastrointestinal tract. Coatingswhich are pH-dependent may be used in accordance with the presentinvention include shellac, cellulose acetate phthalate (CAP), polyvinylacetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, andmethacrylic acid ester copolymers, zein, and the like.

In certain preferred embodiments, the substrate (e.g., tablet core bead,matrix particle) containing the oxymorphone hydrochloride having lessthan 10 ppm of alpha, beta unsaturated ketones thereof is coated with ahydrophobic material selected from (i) an alkylcellulose; (ii) anacrylic polymer; or (iii) mixtures thereof. The coating may be appliedin the form of an organic or aqueous solution or dispersion. The coatingmay be applied to obtain a weight gain from about 2% to about 25% of thesubstrate in order to obtain a desired sustained release profile.Coatings derived from aqueous dispersions are described in detail U.S.Pat. No. 5,273,760, U.S. Pat. No. 5,286,493, U.S. Pat. No. 5,324,351,U.S. Pat. No. 5,356,467, and U.S. Pat. No. 5,472,712.

Alkylcellulose Polymers

Cellulosic materials and polymers, including alkylcelluloses, providehydrophobic materials well suited for coating the beads according to theinvention. Simply by way of example, one preferred alkylcellulosicpolymer is ethylcellulose, although the artisan will appreciate thatother cellulose and/or alkylcellulose polymers may be readily employed,singly or in any combination, as all or part of a hydrophobic coatingaccording to the invention.

Acrylic Polymers

In other preferred embodiments of the present invention, the hydrophobicmaterial comprising the sustained release coating is a pharmaceuticallyacceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate copolymers,ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamide copolymer,poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate)copolymer, polyacrylamide, aminoalkyl methacrylate copolymer,poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers. Ammonio methacrylatecopolymers are well known in the art, and are described as fullypolymerised copolymers of acrylic and methacrylic acid esters with a lowcontent of quaternary ammonium groups.

In order to obtain a desirable dissolution profile, it may be necessaryto incorporate two or more ammonio methacrylate copolymers havingdiffering physical properties, such as different molar ratios of thequaternary ammonium groups to the neutral (meth)acrylic esters.

Certain methacrylic acid ester-type polymers are useful for preparingpH-dependent coatings, which may be used in accordance with the presentinvention. For example, there are a family of copolymers synthesizedfrom diethylaminoethyl methacrylate and other neutral methacrylicesters, also known as methacrylic acid copolymer or polymericmethacrylates, commercially available as Eudragit™ from Rohm Tech, Inc.There are several different types of Eudragit™, for example Eudragit™ Eis an example of a methacrylic acid copolymer that swells and dissolvesin acidic media. Eudragit™ L is a methacrylic acid copolymer which doesnot swell at about pH<5.7 and is soluble at about pH>6. Eudragit™ S doesnot swell at about pH<6.5 and is soluble at about pH>7. Eudragit™ RL andEudragit™ RS are water swellable, and the amount of water absorbed bythese polymers is pH-dependent, however, dosage forms coated withEudragit™ RL and RS are pH-independent.

In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from RohmPharma under the Tradenames Eudragit™ RL30D and Eudragit™ RS30D,respectively. Eudragit™ RL30D and Eudragit™ RS30D are copolymers ofacrylic and methacrylic esters with a low content of quaternary ammoniumgroups, the molar ratio of ammonium groups to the remaining neutral(meth)acrylic esters being 1:20 in Eudragit™ RL30D and 1:40 in Eudragit™RS30D. The mean molecular weight is about 150,000. The code designationsRL (high permeability) and RS (low permeability) refer to thepermeability properties of these agents. Eudragit™ RL/RS mixtures areinsoluble in water and in digestive fluids. However, coatings formedfrom the same are swellable and permeable in aqueous solutions anddigestive fluids.

The Eudragit™ RL/RS dispersions of the present invention may be mixedtogether in any desired ratio in order to ultimately obtain a sustainedrelease formulation having a desirable dissolution profile. Desirablesustained release formulations may be obtained, for instance, from aretardant coating derived from 100% Eudragit™ RL, 50% Eudragit™ RL and50% Eudragit™ RS, or 10% Eudragit™ RL and 90% Eudragit™ RS. Of course,one skilled in the art will recognize that other acrylic polymers mayalso be used, such as, for example, Eudragit™ L.

Plasticisers

In embodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic material, the inclusion of aneffective amount of a plasticiser in the aqueous dispersion ofhydrophobic material will further improve the physical properties of thesustained release coating. For example, because ethyl-cellulose has arelatively high glass transition temperature and does not form flexiblefilms under normal coating conditions, it is preferable to incorporate aplasticiser into an ethylcellulose coating containing sustained releasecoating before using the same as a coating material. Generally, theamount of plasticiser included in a coating solution is based on theconcentration of the film-former, e.g., most often from about 1 wt % toabout 50 wt % of the film-former. Concentration of the plasticiser,however, can only be properly determined after careful experimentationwith the particular coating solution and method of application.

Examples of suitable plasticisers for ethylcellulose include waterinsoluble plasticisers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tributyl citrate, and triacetin, although it ispossible that other water-insoluble plasticisers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used.Triethyl citrate is an especially preferred plasticiser for the aqueousdispersions of ethyl cellulose of the present invention.

Examples of suitable plasticisers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate, tributyl citrate, dibutyl phthalate, andpossibly 1,2-propylene glycol. Other plasticisers that have proved to besuitable for enhancing the elasticity of the films formed from acrylicfilms such as Eudragit™ RL/RS lacquer solutions include polyethyleneglycols, propylene glycol, diethyl phthalate, castor oil, and triacetin.Triethyl citrate is an especially preferred plasticiser for the aqueousdispersions of ethyl cellulose of the present invention.

The addition of a small amount of talc may also help reduce the tendencyof the aqueous dispersion to stick during processing, and may act as apolishing agent.

Sustained Release Osmotic Dosage Form

Sustained release dosage forms according to the present invention mayalso be prepared as osmotic dosage formulations. The osmotic dosageforms preferably include a bilayer core comprising a drug layer(containing the oxymorphone hydrochloride having less than 10 ppm ofalpha, beta unsaturated ketones) and a delivery or push layer, whereinthe bilayer core is surrounded by a semipermeable wall and optionallyhaving at least one passageway disposed therein.

The expression “passageway” as used for the purpose of this invention,includes aperture, orifice, bore, pore, porous element through whichoxymorphone hydrochloride having less than 10 ppm of alpha, betaunsaturated ketones can be pumped, diffuse or migrate through a fibre,capillary tube, porous overlay, porous insert, microporous member, orporous composition. The passageway can also include a compound thaterodes or is leached from the wall in the fluid environment of use toproduce at least one passageway. Representative compounds for forming apassageway include erodable poly(glycolic) acid, or poly(lactic) acid inthe wall; a gelatinous filament; a water-removable poly(vinyl alcohol);leachable compounds such as fluid-removable pore-formingpolysaccharides, acids, salts or oxides. A passageway can be formed byleaching a compound from the wall, such as sorbitol, sucrose, lactose,maltose, or fructose, to form a sustained-release dimensionalpore-passageway. The dosage form can be manufactured with one or morepassageways in spaced-apart relation on one or more surfaces of thedosage form. A passageway and equipment for forming a passageway aredisclosed in U.S. Pat. No. 3,845,770, U.S. Pat. No. 3,916,899, U.S. Pat.No. 4,063,064 and U.S. Pat. No. 4,088,864. Passageways comprisingsustained-release dimensions sized, shaped and adapted as areleasing-pore formed by aqueous leaching to provide a releasing-pore ofa sustained-release rate are disclosed in U.S. Pat. No. 4,200,098 andU.S. Pat. No. 4,285,987.

In certain embodiments the drug layer may also comprise at least onepolymer hydrogel. The polymer hydrogel may have an average molecularweight of between about 500 and about 6,000,000. Examples of polymerhydrogels include but are not limited to a maltodextrin polymercomprising the formula (C₆H₁₂O₅)_(n)H₂O, wherein n is 3 to 7,500, andthe maltodextrin polymer comprises a 500 to 1,250,000 number-averagemolecular weight; a poly(alkylene oxide) represented by, e.g., apoly(ethylene oxide) and a poly(propylene oxide) having a 50,000 to750,000 weight-average molecular weight, and more specificallyrepresented by a poly(ethylene oxide) of at least one of 100,000,200,000, 300,000 or 400,000 weight-average molecular weights; an alkalicarboxyalkylcellulose, wherein the alkali is sodium or potassium, thealkyl is methyl, ethyl, propyl, or butyl of 10,000 to 175,000weight-average molecular weight; and a copolymer of ethylene-acrylicacid, including methacrylic and ethacrylic acid of 10,000 to 500,000number-average molecular weight.

In certain embodiments of the present invention, the delivery or pushlayer comprises an osmopolymer. Examples of an osmopolymer include butare not limited to a member selected from the group consisting of apolyalkylene oxide and a carboxyalkylcellulose. The polyalkylene oxidepossesses a 1,000,000 to 10,000,000 weight-average molecular weight. Thepolyalkylene oxide may be a member selected from the group consisting ofpolymethylene oxide, polyethylene oxide, polypropylene oxide,polyethylene oxide having a 1,000,000 average molecular weight,polyethylene oxide comprising a 5,000,000 average molecular weight,polyethylene oxide comprising a 7,000,000 average molecular weight,cross-linked polymethylene oxide possessing a 1,000,000 averagemolecular weight, and polypropylene oxide of 1,200,000 average molecularweight. Typical osmopolymer carboxyalkylcellulose comprises a memberselected from the group consisting of alkali carboxyalkyl-cellulose,sodium carboxymethylcellulose, potassium carboxymethylcellulose, sodiumcarboxyethylcellulose, lithium carboxymethylcellulose, sodiumcarboxyethyl-cellulose, carboxyalkylhydroxyalkylcellulose,carboxymethylhydroxyethyl cellulose, carboxyethylhydroxyethylcelluloseand carboxymethylhydroxypropylcellulose. The osmopolymers used for thedisplacement layer exhibit an osmotic pressure gradient across thesemipermeable wall. The osmopolymers imbibe fluid into dosage form,thereby swelling and expanding as an osmotic hydrogel (also known as anosmogel), whereby they push the oxymorphone hydrochloride having lessthan 10 ppm of alpha, beta unsaturated ketones thereof from the osmoticdosage form.

The push layer may also include one or more osmotically effectivecompounds also known as osmagents and as osmotically effective solutes.They imbibe an environmental fluid, for example, from thegastrointestinal tract, into dosage form and contribute to the deliverykinetics of the displacement layer. Examples of osmotically activecompounds comprise a member selected from the group consisting ofosmotic salts and osmotic carbohydrates. Examples of specific osmagentsinclude but are not limited to sodium chloride, potassium chloride,magnesium sulphate, lithium phosphate, lithium chloride, sodiumphosphate, potassium sulphate, sodium sulphate, potassium phosphate,glucose, fructose and maltose.

The push layer may optionally include a hydroxypropylalkylcellulosepossessing a 9,000 to 450,000 number-average molecular weight. Thehydroxypropylalkyl-cellulose is represented by a member selected fromthe group consisting of hydroxypropylmethylcellulose,hydroxypropylethylcellulose, hydroxypropylisopropyl cellulose,hydroxypropylbutylcellulose, and hydroxypropylpentylcellulose.

The push layer optionally may comprise a non-toxic colourant or dye.Examples of colourants or dyes include but are not limited to Food andDrug Administration Colourants (FD&C), such as FD&C No. 1 blue dye, FD&CNo. 4 red dye, red ferric oxide, yellow ferric oxide, titanium dioxide,carbon black, and indigo.

The push layer may also optionally comprise an antioxidant to inhibitthe oxidation of ingredients. Some examples of antioxidants include butare not limited to a member selected from the group consisting ofascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, a mixtureof 2 and 3 tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene,sodium isoascorbate, dihydroguaretic acid, potassium sorbate, sodiumbisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate,vitamin E, 4-chloro-2,6-ditertiary butylphenol, alphatocopherol, andpropylgallate.

In certain alternative embodiments, the dosage form comprises ahomogenous core comprising oxymorphone hydrochloride having less than 10ppm of alpha, beta unsaturated ketones, a pharmaceutically acceptablepolymer (e.g., polyethylene oxide), optionally a disintegrant (e.g.,polyvinylpyrrolidone), optionally an absorption enhancer (e.g., a fattyacid, a surfactant, a chelating agent, a bile salt, etc). The homogenouscore is surrounded by a semipermeable wall having a passageway (asdefined above) for the release of the oxymorphone hydrochloride havingless than 10 ppm of alpha, beta unsaturated ketones.

In certain embodiments, the semipermeable wall comprises a memberselected from the group consisting of a cellulose ester polymer, acellulose ether polymer and a cellulose ester-ether polymer.Representative wall polymers comprise a member selected from the groupconsisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di- and tricellulose alkenylates, and mono-, di- andtricellulose alkinylates. The poly(cellulose) used for the presentinvention comprises a number-average molecular weight of 20,000 to7,500,000.

Additional semipermeable polymers for the purpose of this inventioncomprise acetaldehyde dimethycellulose acetate, cellulose acetateethylcarbamate, cellulose acetate methylcarbamate, cellulose diacetate,propylcarbamate, cellulose acetate diethylaminoacetate; semipermeablepolyamide; semipermeable polyurethane; semipermeable sulfonatedpolystyrene; semipermeable cross-linked polymer formed by thecoprecipitation of a polyanion and a polycation, semipermeablecrosslinked polystyrenes, semipermeable cross-linked poly(sodium styrenesulfonate), semipermeable crosslinked poly(vinylbenzyltrimethyl ammoniumchloride) and semipermeable polymers possessing a fluid permeability of2.5×10⁻⁸ to 2.5×10⁻² (cm²/hr atm) expressed per atmosphere ofhydrostatic or osmotic pressure difference across the semipermeablewall. Other polymers useful in the present invention are known in theart including those in Handbook of Common Polymers, Scott, J. R. and W.J. Roff, 1971, CRC Press, Cleveland, Ohio.

In certain embodiments, preferably the semipermeable wall is nontoxic,inert, and it maintains its physical and chemical integrity during thedispensing life of the drug. In certain embodiments, the dosage formcomprises a binder. An example of a binder includes, but is not limitedto a therapeutically acceptable vinyl polymer having a 5,000 to 350,000viscosity-average molecular weight, represented by a member selectedfrom the group consisting of poly-n-vinylamide, poly-n-vinylacetamide,poly(vinyl pyrrolidone), also known as poly-n-vinylpyrrolidone,poly-n-vinylcaprolactone, poly-n-vinyl-5-methyl-2-pyrrolidone, andpoly-n-vinyl-pyrrolidone copolymers with a member selected from thegroup consisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinylfluoride, vinyl butyrate, vinyl laureate, and vinyl stearate. Otherbinders include for example, acacia, starch, gelatin, andhydroxypropylalkylcellulose of 9,200 to 250,000 average molecularweight.

In certain embodiments, the dosage form comprises a lubricant, which maybe used during the manufacture of the dosage form to prevent sticking todie wall or punch faces. Examples of lubricants include but are notlimited to magnesium stearate, sodium stearate, stearic acid, calciumstearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid,sodium stearyl fumarate, and magnesium palmitate.

In certain preferred embodiments, the present invention includes atherapeutic composition comprising an amount of oxymorphonehydrochloride having less than 10 ppm of alpha, beta unsaturated ketonesequivalent to 10 to 40 mg oxymorphone hydrochloride, 25 mg to 500 mg ofpoly(alkylene oxide) having a 150,000 to 500,000 average molecularweight, 1 mg to 50 mg of polyvinylpyrrolidone having a 40,000 averagemolecular weight, and 0 mg to about 7.5 mg of a lubricant.

Suppositories

The sustained release formulations of the present invention may beformulated as a pharmaceutical suppository for rectal administrationcomprising a suitable suppository base, and oxymorphone hydrochloridehaving less than 10 ppm of alpha, beta unsaturated ketones. Preparationof sustained release suppository formulations is described in, e.g.,U.S. Pat. No. 5,215,758.

Prior to absorption, the drug must be in solution. In the case ofsuppositories, solution must be preceded by dissolution of thesuppository base, or the melting of the base and subsequent partition ofthe drug from the suppository base into the rectal fluid. The absorptionof the drug into the body may be altered by the suppository base. Thus,the particular suppository base to be used in conjunction with aparticular drug must be chosen giving consideration to the physicalproperties of the drug. For example, lipid-soluble drugs will notpartition readily into the rectal fluid, but drugs that are onlyslightly soluble in the lipid base will partition readily into therectal fluid.

Among the different factors affecting the dissolution time (or releaserate) of the drugs are the surface area of the drug substance presentedto the dissolution solvent medium, the pH of the solution, thesolubility of the substance in the specific solvent medium, and thedriving forces of the saturation concentration of dissolved materials inthe solvent medium. Generally, factors affecting the absorption of drugsfrom suppositories administered rectally include suppository vehicle,absorption site pH, drug pKa, degree of ionisation, and lipidsolubility.

The suppository base chosen should be compatible with the active of thepresent invention. Further, the suppository base is preferably non-toxicand non-irritating to mucous membranes, melts or dissolves in rectalfluids, and is stable during storage.

In certain preferred embodiments of the present invention for bothwater-soluble and water-insoluble drugs, the suppository base comprisesa fatty acid wax selected from the group consisting of mono-, di- andtriglycerides of saturated, natural fatty acids of the chain length C₁₂to C₁₈.

In preparing the suppositories of the present invention other excipientsmay be used. For example, a wax may be used to form the proper shape foradministration via the rectal route. This system can also be usedwithout wax, but with the addition of diluent filled in a gelatincapsule for both rectal and oral administration.

Examples of suitable commercially available mono-, di- and triglyceridesinclude saturated natural fatty acids of the 12-18 carbon atom chainsold under the trade name Novata™ (types AB, AB, B, BC, BD, BBC, E, BCF,C, D and 299), manufactured by Henkel, and Witepsol™ (types H5, H12,H15, H175, H185, H19, H32, H35, H39, H42, W25, W31, W35, W45, S55, S58,E75, E76 and E85), manufactured by Dynamit Nobel.

Other pharmaceutically acceptable suppository bases may be substitutedin whole or in part for the above-mentioned mono-, di- andtriglycerides. The amount of base in the suppository is determined bythe size (i.e. actual weight) of the dosage form, the amount of base(e.g., alginate) and drug used. Generally, the amount of suppositorybase is from about 20% to about 90% by weight of the total weight of thesuppository. Preferably, the amount of suppository base in thesuppository is from about 65% to about 80%, by weight of the totalweight of the suppository.

ADDITIONAL EMBODIMENTS

The oxymorphone hydrochloride having less than 10 ppm of alpha, betaunsaturated ketones may be used as a substitute for the oxymorphonehydrochloride in any existing commercial product such as, e.g., Opana™,Opana ER™ and Numorphan™. Such formulations are listed in the FDA OrangeBook.

EXAMPLES

The invention will now be illustrated by the following examples, showingthe synthesis of the high purity oxymorphone, starting from oripavine.

FIG. 1 is the Powder X-Ray Diffraction pattern collected for a hydratedoxymorphone hydrochloride product made according to Example 3.2D.

Example 1.1A Hydroxylation of Oripavine to 14-hydroxymorphinone

1 kg oripavine is added with stirring to a reaction vessel containing2.76 kg of formic acid and 0.53 kg water, and stirring is continueduntil the oripavine is completely dissolved, and the temperature remainsin the range 20-30° C. Subsequently, 0.36 kg of 35 wt % hydrogenperoxide solution is added, and the reaction mixture is stirred forthree hours or more, whilst maintaining the temperature in the range20-35° C. The reaction vessel is cooled to 10° C. and 7.12 litres ofdilute ammonium hydroxide is added slowly, whilst maintaining thereaction mixture below 40° C. If necessary, the pH of the reactionmixture is adjusted to the range 8 to 10, with more dilute ammoniumhydroxide solution or hydrochloric acid as appropriate, and stirring iscontinued for 3-5 hours.

A precipitate of product 14-hydroxymorphinone is formed and filteredoff. The precipitate is washed with water until colourless and thendried to a damp cake and collected for the next stage.

Example 1.1B Formation of Oxymorphone Base

A hydrogenation vessel is charged with kg litre water and 0.73 kg aceticacid before adding 1 kg of 14-hydroxymorphinone prepared as in Example1.1A and the mixture stirred until clear. 40 g of wet 10% Pd on carboncatalyst is added under a stream of nitrogen, and hydrogen supplied at35-40 psi (2.41-2.76 bar). The temperature is maintained at 30±5° C.until hydrogen uptake stops, then the vessel is maintained at 35-40 psi(2.41-2.76 bar) and 30±5° C. for 3-4 hours. The reaction vessel iscooled to less than 25° C. and a sample subjected to HPLC to check for14-hydroxymorphinone. If the 14-hydroxymorphinone area detected by HPLCis >0.1%, the hydrogenation is repeated.

Once it is assessed that the reaction is complete, the catalyst isfiltered off, the pH of the filtrate is adjusted to pH 9 using ammoniumhydroxide solution, the product precipitates and is isolated byfiltration and dried under vacuum. The product is dissolved indichloromethane/methanol (9:1 v/v) and slurried in florisil, filtered,and the filtrate is distilled to exchange to n-propanol. The n-propanolmixture is cooled and the product precipitates and is collected byfiltrationin 66% yield. A sample of product is tested by HPLC for alpha,beta unsaturated ketones, and is found to contain 0.51% by areameasurement.

Example 1.1C Formation of Highly Pure Oxymorphone Hydrochloride

A reaction vessel is charged with 1 kg of oxymorphone base, prepared asin Example 1.1B, together with 2.05 kg of absolute alcohol and 0.66 kgof water. The mixture is heated to 60±2° C. and stirred to form aslurry. A hydrochloric acid solution prepared from 0.66 kg concentratedhydrochloric acid, 0.24 kg of water and 0.31 kg of absolute alcohol isadded to the oxymorphone base slurry and the pH checked to ensure thatit is <1.0. 40 g of 10% Pd on carbon catalyst water-wet paste is addedunder a stream of nitrogen to the reaction mixture and the mixture ishydrogenated at 35±5 psi (2.41 bar) for 20 hours whilst maintaining atemperature of 65±3° C. The reaction mixture is filtered whilst hotthrough Celite and a 0.2 μm polish filter. The filtrate is cooled to0-5° C. over 2-3 hours, and stirred for a further 2 hours to formoxymorphone hydrochloride as a precipitate. The precipitate is washedwith absolute alcohol then dried. Yield is 80%.

A sample of the product is tested by HPLC for the presence of alpha,beta unsaturated ketones, and is found to contain 6.2 ppm.

Example 1.2A Hydroxylation of Oripavine to 14-hydroxymorphinone

40 g of Oripavine is added with stirring to a reaction vessel containing30 g of water and 85 g of formic acid, and stirring continued untiloripavine is completely dissolved. The temperature remains in the range20-30° C. Subsequently, 17.72 g of 30 wt % hydrogen peroxide solution isadded, and the reaction mixture is stirred for three hours or more,whilst maintaining the temperature in the range 20-35° C. The reactionmixture is cooled to <20° C. and 335 mL of dilute ammonium hydroxide isadded slowly, whilst maintaining the reaction mixture below 32° C. Ifnecessary, the pH of the reaction mixture is adjusted to 9.0, with moredilute ammonium hydroxide solution or hydrochloric acid as appropriate,and stirring is continued for 2 hours at 20 C and 2 hours at 4-5° C.

A precipitate of 14-hydroxymorphinone is formed and filtered off. Theprecipitate is washed with water and then dried to a damp cake andcollected for the next stage.

Example 1.2B Formation of Oxymorphone Base

A hydrogenation vessel is charged with 148 g of water, 90.6 g of aceticacid, and 250 g of damp 14-hydroxymorphinone (48% water content),prepared as in Example 1.2A. The mixture is stirred until clear then1.34 g of 10% Pd on carbon catalyst (dry weight) in the form of a pasteis added under a stream of nitrogen. The hydrogenation vessel is flushedwith nitrogen and hydrogen respectively, and then the reaction mixtureis hydrogenated at 30° C. and 35 psi (2.41 bar) for 5 hours. An inprocess test by HPLC indicates an 14-hydroxymorphinone area of 0.07%.

Once it is assessed that the reaction is complete, the catalyst isfiltered off through a pad of celite, and the celite cake is washed with25 mL water. The filtrate is cooled to 0-5° C. and the pH is adjusted to9.5±0.5 with 1:1 mixture (V/V) of concentrated ammonium hydroxide andwater. The precipitate is stirred at 0-5° C. for one hour and isolatedby filtration. The crude product is dried in vacuum oven at 50° C. toafford 113 g (86.9% yield) of light beige solid. A sample of product istested by HPLC for alpha, beta unsaturated ketone, and is found tocontain 0.27% by area measurement.

113 g of crude oxymorphone base is taken up in 1.13 L ofdichloromethane/methanol (9:1, v/v). 113 g of florisil is added to thesolution and the mixture is stirred for 12 hours. The mixture isfiltered through a pad of 113 g of florisil, and the florisil cake isrinsed with 120 mL of dichloromethane/methanol. The solvent is removedby distillation and then switched to n-propanol. The batch is cooled to0-5° C. and stirred for 1 hour to precipitate the oxymorphone base,which is filtered off, washed with cold n-propanol, and dried in avacuum oven to afford 67.2 g (59.47%) of white solids.

A sample of product is tested by HPLC for alpha, beta unsaturatedketones, and is found to contain 0.027% by area measurement.

Example 1.2C Formation of Highly Pure Oxymorphone Hydrochloride

A reaction vessel is charged with 50.1 g of oxymorphone base, preparedas in Example 1.2B, together with 120 g of absolute alcohol. The mixtureis heated to 60±2° C. and stirred to form a slurry. A hydrochloric acidsolution prepared from 32.7 g concentrated hydrochloric acid and 33.6 gof water is added to the oxymorphone base slurry and the pH is checkedto ensure that it is <1.0. 2.0 g of 10% Pd on carbon catalyst water-wetpaste is added under a stream of nitrogen to the reaction mixture andthe mixture is hydrogenated at 35 psi (2.41 bar) for 20 hours whilstmaintaining a temperature of 65° C. The reaction mixture is filteredwhilst hot through Celite. The filtrate is cooled to 0-5° C. over 2-3hours, and stirred for a further 2 hours to form oxymorphonehydrochloride as a precipitate. The precipitate is filtered off, washedwith absolute alcohol and then dried to afford white crystals in 77%yield.

A sample of the product is tested by HPLC for the presence of alpha,beta unsaturated ketones, and is found to contain 1.1 ppm.

The above method may be varied by the skilled person whilst stillmaintaining excellent purity of the product oxymorphone hydrochloride,and examples of such variations follow.

Example 2.1B Reduction of 14-hydroxymorphinone to Oxymorphone Base

A hydrogenation vessel is charged with 2.5 kg of water and 0.73 kg ofacetic acid and 1 kg of 14-hydroxymorphinone is added to the vessel. Thereaction mixture is stirred until a clear solution is obtained before 40g of wet 10% Pd on carbon catalyst is added under a stream of nitrogen.Hydrogen is supplied at 35-40 psi (2.41-2.76 bar). The temperature ismaintained at 30±5° C. until hydrogen uptake stops, then the vessel ismaintained at 35-40 psi (2.41-2.76 bar) and 30±5° C. for 3-4 hours. Thereaction vessel is cooled to less than 25° C. and a sample subjected toHPLC to check for 14-hydroxymorphinone. If the 14-hydroxymorphinone areadetected by HPLC is >0.1%, the hydrogenation is repeated.

Once it is assessed that the reaction is complete, the catalyst isfiltered off, dichloromethane/methanol (9:1 v/v) is added to thefiltrate and the mixture is adjusted to pH 9-10 by adding ammoniumhydroxide solution. The dichloromethane/methanol phase is separate,slurried in florisil, filtered, and the filtrate is distilled toexchange to n-propanol. The n-propanol mixture is cooled and the productprecipitates and is collected by filtration in 73% yield. A sample ofproduct is tested by HPLC for alpha, beta unsaturated ketones, and isfound to contain 0.32% by area.

Example 2.2B Reduction of 14-hydroxymorphinone to Oxymorphone Base

A hydrogenation vessel is charged with 35 g of water, 17 g of aceticacid and 38.08 g of 14-hydroxymorphinone, prepared in Example 1.2A. Thereaction mixture is stirred until a clear solution is obtained before1.8 g of wet 5% Pd on carbon catalyst is added under a stream ofnitrogen. Hydrogen is supplied at 35-40 psi (2.41-2.76 bar). Thetemperature is maintained at 30±5° C. until hydrogen uptake stops, thenthe vessel is maintained at 35-40 psi (2.41-2.76 bar) and 30±5° C. for 4hours. The reaction vessel is cooled to less than 25° C., and a sampleis analysed by HPLC to check for 14-hydroxymorphinone. The14-hydroxymorphinone area detected by HPLC is 0.26%.

Once it is assessed that the reaction is complete, the catalyst isfiltered off and the cake is washed with 15 mL of water. 180 mL ofdichloromethane/methanol (9:1, v/v) are added to the filtrate and the pHof the mixture is adjusted to pH 9-10 by adding concentrated ammoniumhydroxide. The dichloromethane/methanol layer is separated and purifiedby slurrying with ca. 20 g florisil. The slurry is filtered and thefiltrate is distilled to exchange into n-propanol, and the mixture iscooled to 0-5° C. and stirred for 1-2 hours to precipitate oxymorphonebase, which is isolated by filtration. The oxymorphone base is thenslurried from n-propanol providing product in 74% yield. A sample ofproduct is tested by HPLC for alpha, beta unsaturated ketones, and isfound to contain 0.32% by area.

Example 2.2C Formation of Highly Pure Oxymorphone Hydrochloride

A reaction vessel is charged with 2.5 g of oxymorphone base, prepared asin Example 2.2B, together with 7.5 mL of absolute alcohol, 2.5 g ofwater and 1.66 g of concentrated hydrochloric acid. The mixture isheated to 50-60° C. and a solution results. The pH is checked to ensurethat it is <1.0. 0.111 g of 10% Pd on carbon catalyst water-wet paste isadded under a stream of nitrogen to the reaction mixture and the mixtureis hydrogenated at 35±5 psi (2.41 bar) for 21 hours whilst maintaining atemperature of 65±3° C. The reaction mixture is filtered whilst hotthrough a 0.45 μm filter. The filtrate is cooled to 0-5° C. over 2-3hours, and stirred for a further 2 hours to form oxymorphonehydrochloride as a precipitate. The precipitate is filtered off, washedwith cold absolute alcohol and dried under vacuum to afford whitecrystals in 77% yield.

A sample of the product is tested by HPLC for the presence of alpha,beta unsaturated ketones, and is found to contain 2.8 ppm.

Example 3.1B Reduction of 14-hydroxymorphinone to OxymorphoneHydrochloride

The procedure for forming the oxymorphinone free base is followed asshown above, but instead of isolating the free base from adichloromethane/methanol solution, 0.35 volume equivalents of 3Nhydrochloric acid are added (vs the volume of thedichloromethane/methanol solution), the reaction mixture is stirred,allowed to stand, and the aqueous layer (contains the product) isseparated from the organic layer. The aqueous layer is distilled undervacuum to remove ca. 50% of the volume, and then the remaining solutionis cooled over 2 hour to 20-25° C., stirred for 1-2 hours, cooled to0-5° C. and stirred 2-3 hours. The white solids that form duringstirring are filtered off and washed with cold isopropanol. The yield is64% and the product contains 0.34% of alpha, beta unsaturated ketones.

Example 3.1C Purification of Oxymorphone Hydrochloride

Using an analogous process to Example 1.1C, but starting from theproduct of Example 3.1B, purified oxymorphone hydrochloride is obtainedin a yield of 92% and having an undetectable content of alpha, betaunsaturated ketones.

Example 3.2C Preparation of Highly Pure Oxymorphone Hydrochloride

A reaction vessel is charged with 5.05 g of oxymorphone hydrochloride,prepared in Example 3.1B, together with 13.5 mL of absolute alcohol, 4.5mL of water and 1.51 g of concentrated hydrochloric acid. The mixture isheated to 50-60° C. and a solution results. The pH is checked to ensurethat it is <1.0. 0.21 g of 10% Pd on charcoal catalyst water-wet pasteis added under a stream of nitrogen to the reaction mixture and themixture is hydrogenated at 35±5 psi (2.41 bar) for 20 hours whilstmaintaining a temperature of 65±3° C. The reaction mixture is filteredwhilst hot through a 0.45 μm filter. The filtrate is cooled to 0-5° C.over 2-3 hours, and stirred for a further 2 hours to form a precipitate.The precipitate is collected by filtration, washed with cold absolutealcohol then dried. Yield is 92%.

A sample of the product is tested by HPLC and found to have anundetectable content of alpha, beta unsaturated ketones.

Without changing the basic process steps, but with small variations inthe process steps for starting materials, such as isolation or not ofsuch starting materials, and utilising the essential reductionrequirements of the invention for the final step to the purifiedoxymorphone hydrochloride, other products have been obtained with levelsof alpha, beta unsaturated ketones of 3.8 ppm, 1.7 ppm, 6.2 ppm, 6.9ppm, 2.8 ppm, 3.1 ppm, 0.9 ppm, 6.0 ppm and another undetectable, orzero.

Example 3.2D Hydration of Oxymorphone Hydrochloride

A drying dish is charged with oxymorphone hydrochloride, prepared as inExample 1.1C, 1.2C, 2.2C, 3.1C or 3.2C, which contains about 5-13 wt %of ethanol. The sample is placed in a vacuum oven along with a dishcontaining 100 mL of water. A vacuum is applied at 24-29 in Hg and theoven maintained at 20-40° C. for 24 hours. An ethanol-free or lowethanol (approx. 0.04 wt %) product is afforded containing about 10-13wt % of water. The water absorbed by the sample may be removed in avacuum oven at 50-55° C. The drying process is stopped when theproduct's KF is 6-8 wt %. The final hydrated oxymorphone hydrochlorideaffords a uniform polymorph with a consistent X-ray diffraction pattern.

1. An oxymorphone hydrochloride product having less than 10 ppm, asmeasured by HPLC, of alpha, beta unsaturated ketones.
 2. A productaccording to claim 1, wherein the content of alpha, beta unsaturatedketones is less than 5 ppm.
 3. A product according to claim 1, whereinthe ketones comprise 14-hydroxymorphinone.
 4. A pharmaceuticalformulation comprising at least one pharmaceutically acceptableexcipient and an oxymorphone hydrochloride product according to claim 1.5. A method of treating pain comprising administering a pharmaceuticalformulation according to claim 4 to a patient in need thereof.
 6. Amethod of purifying oxymorphone hydrochloride to yield a productaccording to claim 1, comprising reducing a starting materialoxymorphone hydrochloride in a strongly acid water and alcohol solventreaction medium, using gaseous hydrogen at a temperature in the rangefrom 60 to 70° C.
 7. A method according to claim 6, wherein thereduction is carried out for a period of at least 20 hours.
 8. A methodaccording to claim 6, wherein the reduction is carried out for a periodof from 1 to 20 hours.
 9. A method according to claim 6, wherein thereaction medium has a pH of less than
 1. 10. A method according to claim6, wherein the acid is hydrochloric acid.
 11. A method according toclaim 6, wherein the temperature is approximately 65° C.
 12. A methodaccording to claim 6, wherein the starting material oxymorphonehydrochloride has not been isolated from a reaction mixture in which itis formed.
 13. A method according to claim 6, wherein the startingmaterial oxymorphone hydrogen chloride has been prepared by a process ofreduction of 14-hydroxymorphinone.
 14. A method according to claim 13,wherein the starting material 14-hydroxymorphinone has been prepared bya process of hydroxylating oripavine.
 15. A method according to claim14, wherein the starting material oripavine is derived from concentratedpoppy straw.
 16. A method according to claim 15, wherein theconcentrated poppy straw is derived from a high-Thebaine-yielding strainof poppy.
 17. A method according to claim 6, comprising the additionalstep of removing residual alcohol molecules from within the crystalstructure of the oxymorphone hydrochloride by exposing the oxymorphonehydrochloride to water vapour, such that the residual alcohol moleculesare displaced with water molecules.
 18. A method according to claim 17,comprising the additional step of removing some of the water moleculesfrom within the crystal structure of the oxymorphone hydrochloride byvacuum hydration of the oxymorphone hydrochloride.
 19. A methodaccording to claim 17, comprising the additional step of removing someof the water molecules from within the crystal structure of theoxymorphone hydrochloride by heating the oxymorphone hydrochloride in avacuum to a temperature in the range of from 50 to 55° C.
 20. A hydratedoxymorphone hydrochloride product, having less than 10 ppm, as measuredby HPLC, of alpha, beta unsaturated ketones and a KF of 6-8 wt %,wherein said product is produced by a method comprising reducing astarting material oxymorphone hydrochloride in a strongly acid water andalcohol solvent reaction medium, using gaseous hydrogen at a temperaturein the range from 60 to 70° C., and removing residual alcohol moleculesfrom within the crystal structure of the oxymorphone hydrochloridefollowing reducing by exposing the oxymorphone hydrochloride to watervapour, such that the residual alcohol molecules are displaced withwater molecules.
 21. A hydrated oxymorphone hydrochloride product,having less than 10 ppm, as measured by HPLC, of alpha, beta unsaturatedketones and having peaks within the following 2θ ranges when analysed byPowder X-Ray Diffraction: 8.5-9.5, 11.0-12.0, 11.5-12.5, 12.4-13.4,15.2-16.2, 17.6-18.6, 19.3-20.3, 19.9-20.9, 24.6-25.6, 24.9-25.9,29.0-30.0 and 31.0-32.0, wherein said product is produced by a methodcomprising reducing a starting material oxymorphone hydrochloride in astrongly acid water and alcohol solvent reaction medium, using gaseoushydrogen at a temperature in the range from 60 to 70° C., and removingresidual alcohol molecules from within the crystal structure of theoxymorphone hydrochloride following reducing by exposing the oxymorphonehydrochloride to water vapour, such that the residual alcohol moleculesare displaced with water molecules.
 22. A product according to claim 2,wherein the ketones comprise 14-hydroxymorphinone.